E-drug: Comments urgently needed on CIOMS ethics document
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[Warning, long message. HH]
Dear Colleagues:
I am writing to urge you to submit comments on the draft revised
version of the Council for International Organizations of Medical
Sciences (CIOMS) International Ethical Guidelines for Biomedical
Research Involving Human Subjects as soon as possible. This is one
of the more important international ethics documents. Both the
current version and the proposed revisions can be found at
http://www.cioms.ch. Comments are due this Monday, July 16,
though it is possible that comments submitted somewhat after this
date will also be accepted. I apologise for the late notice, but I
wanted to include Public Citizen's comments along with our request
to you to comment. If you will miss the July 16 deadline, I'd
recommend sending a note to CIOMS at cioms@who.ch. Please
send me a copy of any comments you submit at plurie@citizen.org.
The primary purpose of the CIOMS document is to recoup the
ground the research industry lost when the Declaration of Helsinki
was strengthened in October 2000
(http://www.wma.net/e/policy/17-c_e.html). In particular, the
revised CIOMS document would:
a. Permit the withholding of known effective therapies from
patients in clinical trials on the basis of their poverty, in certain
circumstances
b. Regardless of participant poverty, expand the use of placebos in
studies of some serious conditions for which there are known
effective therapies
c. Remove the requirement that persons in underdeveloped
communities be the subject of research only if less vulnerable
communities were somehow unsuitable
d. Not require adequate conflict of interest disclosures to the
ethics committee and patient
e. Allow restrictions on patients' ability to collect compensation
for injuries incurred during the study.
Public Citizen's comments on this draft are both attached to this
email in Microsoft Word and can be found at
http://www.citizen.org/hrg/PUBLICATIONS/1580.htm. (Over the
weekend of July 14 and 15 they will be at
http://www.citizen.org/hrg/1580.htm, but will be moved to the
address above on Monday.) Please do send comments as soon as
possible, with a copy to me. Also, please post this message on all
appropriate listserves.
Yours sincerely,
Peter Lurie, MD, MPH
Deputy Director
Public Citizen's Health Research Group
1600 20th Street, NW
Washington, DC 20009
Phone: (202)588-7781
Fax: (202)588-7796
Email: plurie@citizen.org
Web address: http://www.citizen.org
--------------------
July 13, 2001
Dr. Jack Bryant
President
Council for International Organizations of Medical Sciences
c/o World Health Organization
CH-1211 Geneva 27
Switzerland
Fax: (41-22) 791 31 11
Email: cioms@who.ch
Dear Dr. Bryant:
The current draft revision of the Council for International
Organizations of Medical Sciences (CIOMS) International Ethical
Guidelines for Biomedical Research Involving Human Subjects
should be called what it is: a bald-faced and dangerous attempt to
reverse the gains in the protection of research participants
accomplished in the October 2000 version of the World Medical
Association's (WMA's) Declaration of Helsinki (DOH). The
pharmaceutical industry and its allies in the U.S. government and
academia failed in their efforts to insert the "standard of care
argument" (researchers are obligated to provide to research
participants no more treatment than what is otherwise available
locally) into the DOH. They are now apparently hoping that through
the CIOMS process they can accomplish this. The current draft is
also an assault on the more general restrictions on placebo use in
clinical trials that were also part of the revised DOH. Historically,
the CIOMS document has often been seen as an elaboration on the
Declaration of Helsinki. Yet the current draft goes out of its way to
contradict the DOH, particularly on the standard of care issue; other
important elements of the DOH are simply ignored. The apparent
intent is to create a "war of the documents," so that researchers
will be able to pick a study design acceptable to them and then
have an array of different ethical codes from which to justify their
behavior (document shopping?). To an extent, this has already been
accomplished through the International Conference on
Harmonisation (ICH); its monograph on Choice of Control Group in
Clinical Trials is also intended to bolster the inappropriate use of
placebos and is actively hostile toward active-controlled trials). Our
critique of a draft of that document is attached.
Guideline 2: The research protocol (New Guideline)
This new section is mainly acceptable, except that it is insufficiently
prescriptive on conflict of interest. The DOH requires that "The
researcher should also submit to the [ethical review] committee, for
review, information regarding funding, sponsors, institutional
affiliations, other potential conflicts of interest and incentives for
subjects." (Article 13) With researchers (and even universities) now
commonly owning stock in the companies for which they are
conducting research or sitting on their advisory boards, such
disclosure is critical. Yet CIOMS requires less than both the DOH
and what is necessary; the protocol need only include "The
organization that is sponsoring the research and a detailed account
of the sponsor's financial commitments to the research institution,
the researchers, the research subjects, and, when appropriate, the
community." Thus, relationships between the researcher and the
sponsor that are outside the particular study in question would not
need to be disclosed in the protocol.
In our view, in certain circumstances disclosure would not be
enough. Some conflicts are so crass that they should simply be
precluded, not "managed," in the currently popular vernacular.
There is growing evidence of the relationship between funding
source and reported research outcome. Except for investments of
minimal value, therefore, researchers should not be allowed to
conduct research for companies in which they have investments.
Finally, although the DOH has an affirmative requirement for
reporting adverse events to the Institutional Review Board (IRB)
(Article 13), we see no mandate for this in the current draft of the
CIOMS document.
Guideline 3: Ethical review committees (Old Guideline 14)
The discussion of this Guideline goes well beyond legitimate ethical
topics to include a plea for a "hands-off" approach to regulation:
"Sanctions imposed by institutional, governmental, professional or
other authorities possessing disciplinary power should be employed
as a last resort. Preferred methods of control include cultivation of
an atmosphere of mutual trust, and education and support to
promote in researchers and in sponsors the capacity for ethical
conduct of research." Such a regulatory policy may be desirable for
the research industry (including the IRB industry), but it is poor
public policy and inappropriate in an ethics document. Surely, each
country should be free to set its own regulatory policies? Is CIOMS
not recommending a form of Regulatory Imperialism?
The DOH clearly requires that "Reports of experimentation not in
accordance with the principles laid down in this Declaration should
not be accepted for publication." (Article 27) The draft CIOMS
document, on the other hand, seems intent on watering this down:
"Editors should consider refusal to publish the results of research
conducted unethically, and drug regulatory authorities should
consider refusal to accept unethically obtained data submitted in
support of an application for marketing authorization of a product.
Such sanctions, however, deprive of benefit not only the errant
researcher or sponsor but also that segment of society intended to
benefit from the research; such possible consequences merit careful
consideration."
Finally, the ability of IRBs to act independently would be enhanced
if they were required to include scientific representatives from other
relatively nearby institutions.
Guideline 6: Research in populations and communities with limited
resources (Old Guideline 8)
The most important aspect of this draft Guideline is not what is
present, but rather what was excised from the current CIOMS
document: "persons in underdeveloped communities will not
ordinarily be involved in research that could be carried out
reasonably well in developed communities." Of course, research
can only be carried out in countries where the disease is reasonably
prevalent. Developing country research is also readily justified if
there is a clear, scientifically based reason to believe that local
social conditions, viral strains or human genetics differ enough from
those in developed countries to likely change the study results
significantly. But, as a practical matter, the clear result of this
change in language (and, we fear, its intent) is to open the
developing world up to studies that could easily be conducted in
the industrialized world: studies of hypertension, diabetes or some
common infectious conditions. Particularly because practically all
the important recommendations in the current draft come handily
equipped with exceptions, a likely result is a major increase in
studies that could easily be done in an industrialized country, but
where the participants are denied optimal medical care and the
products are not made available afterward. The benefits to the
pharmaceutical industry are obvious: potentially lower costs, less
red tape, larger pools of "na�ve" subjects and lower ethical
requirements. Thanks to the exceptions in the draft document,
there is simply no guarantee of benefit to either the developing
country volunteers or their countrymen and women.
The DOH makes clear that the poor are vulnerable and thus must be
protected from exploitation: "Some research populations are
vulnerable and need special protection. The particular needs of the
economically and medically disadvantaged must be recognized."
(Article 8) Although there are obviously different aspects to their
vulnerability, it is interesting that the draft CIOMS document has
retained the requirement for seeking alternative research
populations to children and those who cannot give informed
consent due to a mental disorder (Guidelines 14 and 15), but has
excised this requirement for residents of developing countries.
It is encouraging that the notion that effective interventions must be
made "reasonably available" after the trial is retained in the current
draft. In fact, it is now supported, for the first time, by a discussion
of prior agreements, which is a step forward.
Guideline 7: Placebo-controlled studies (New Guideline)
The central thrust of the new draft CIOMS document is to dilute the
revised DOH's recommendations on placebo use. Ever since the
DOH required that "The benefits, risks, burdens and effectiveness
of a new method should be tested against those of the best current
prophylactic, diagnostic, and therapeutic methods," (Article 29) the
research industry and their flag-bearers at the U.S. Food and Drug
Administration have been leading the charge to reverse this
provision. To a certain extent, they have a point. As we have
frequently asserted, there is a legitimate role for the use of placebos
even when effective treatment has been identified, as long as the
disease in question is mild. Placebo-controlled trials of treatments
for mild headache, seasonal rhinitis and cough are acceptable. To
the extent that the current DOH would preclude studies of these
conditions, we agree that it should be modified.
But the commentary on Guideline 7 would include a host of other
classes of drugs for which placebo-controlled trials would be
deemed acceptable: analgesics (not only mild analgesics [which
would be acceptable] but, at least as written, powerful ones such
as morphine), anti-emetics (at least as written, including for
vomiting due to chemotherapy) and to "prevent diseases caused by
smoking or other harmful habits related to lifestyle." There are two
problems with this list. First, the issue in deciding the
appropriateness of placebo use is not the drug class, but the
severity of the condition being treated and the effectiveness of
existing therapy. Second, it is completely inappropriate to allow
potentially more dangerous studies to be conducted on patients
simply because the patient's lifestyle may have contributed to their
risk for a disease. This kind of "blame-the-victim" mentality has no
place in any document, let alone a document billing itself as an
ethics document. We should remember that the issue of whether
conditions are considered to be related to lifestyle has deep social
and historical roots. It is not so long ago that schizophrenia was
thought to be a consequence of the patient's lifestyle. Even in the
recent past, injection drug users seeking treatment for opiate
addiction have been randomized to placebos, despite the existence
of methadone. Placebos should be deemed appropriate based on
the severity of the disease and the effectiveness of current
treatment � not on often evidence-free judgments about whether
the patient is making a choice to engage in the lifestyle.
The other obvious purpose of Guideline 7 is to make it easier for
researchers to use the poverty of their participants to justify the
withholding of effective therapies. A variety of statistical arguments
have been made to support this unethical position; we will not
critique them here, but rather attach our comments on the ICH
guideline on this subject.3 The second major justification for
placebo use in this setting is that an active-controlled study may, in
the words of the draft, "yield no reliable scientific results."
Obviously, "reliable" is a subjective judgment, permitting the
researchers to assert that results obtained through an
active-controlled trial fall short of the magical placebo-controlled
trial "gold standard" and are therefore unreliable.
But the real question is whether an alternative trial design would
provide adequate results, while treating all patients. Let us revisit
the issue of the Thailand and African perinatal HIV prevention
studies, in which the placebo-controlled trial was said by the trials'
defenders to be the only way to obtain reliable results. Ironically,
the U.S. National Institutes of Health, which funded more of these
unethical trials than any agency, also funded an active-controlled
trial. In that study, the researchers randomly assigned 1,437
HIV-positive pregnant women to groups in which the women
received either long (12 weeks) or short (5 weeks) regimens of AZT
before delivery and the infants received either long (6 weeks) or
short (3 days) regimens of AZT. There were thus four groups:
long-long (similar to a regimen called ACTG 076 proved effective in
the U.S. and France in 1994); long-short; short-long; and
short-short. All women received AZT during labor, usually by
mouth. The HIV transmission rate in the short-short arm (10.5%)
was so high that the researchers prematurely terminated that arm.
Even so, the short-short arm was so much better than the placebo
arms in all of the unethical studies (and better than the rates of
transmission in other non-treatment studies conducted before AZT
was proved effective for this purpose) that there was no difficulty
concluding that short-short was better than nothing. The placebo in
the other studies was therefore unnecessary and dangerous. The
transmission rates for the long-long (6.5%), long-short (4.7%) and
short-long (8.6%) were statistically indistinguishable. The study
provides clinicians with much better guidance as to which part of
the AZT regimen is critical than do most of the other
placebo-controlled trials.
It is interesting, too, that representatives of the U.S. National
Bioethics Advisory Commission (NBAC), which endorsed limited
exceptions to the DOH's position on placebo use, have rejected the
standard of care argument when it applies to life-threatening
conditions. The only justification for exceptions to the DOH, they
write, would be situations "in which the only useful research
design, from the host country's perspective, required a less
effective intervention in the control group, if the condition being
studied was not life-threatening and if the trial received approval
from an ethics review committee in the host country as well as one
in the United States." (emphasis added) They then go on to discuss
the notorious Surfaxin trial (which would have randomized some
infants with often fatal Respiratory Distress Syndrome to placebo
instead of one of four approved surfactants), concluding that "In
studies of this kind � involving a disease that is life-threatening and
one for which an established, effective treatment is available � a
placebo control is not permissible."
Let us consider another example. For years it has been known that
treatment with at least some antihypertensive medications can
reduce mortality. Yet between 1987 and 1990, Bayer-funded
researchers in China compared the efficacy of nifedipine to placebo
in 1600 patients. The result was 45 more cardiovascular events in
the untreated group (77 in the placebo group vs. 32 in the
nifedipine group). Such a study would (we hope) never be
countenanced in an industrialized country. Is this the new face of
medical research that CIOMS wishes to endorse?
As scientists and persons interested in ethics, we should shy away
from developing ethical standards based on terms such as
"standard of care" that have no scientific meaning but are instead
reflective of economic concerns. From a scientific perspective, there
are only two kinds of medicines: those that have been proved to
work and those that haven't. The DOH assures all patients of the
former, while the proposed CIOMS document will consign some
patients (specifically poor patients) to the latter. This is not
standard of care; it is substandard care and, at times, no care at all.
Guideline 9: Essential information for prospective research subjects
(Old Guideline 2)
The CIOMS draft fails to require two crucial pieces of information:
1. Investments of the researchers and the university in the company
whose product is being tested and service on company advisory
committees (see our comments on Guideline 2); and 2. That the
participants be told the study results. The draft simply requires that
participants learn whether or not they will be told the study results.
Participants who have put their bodies on the line for science
deserve better than that.
The draft also misses a golden opportunity to argue for tests of
comprehension of the information provided, instead of the mere
signing of often-incomprehensible and sometimes misleading
documents. We believe that, particularly in large clinical trials, a
random sample of participants should actually be surveyed to see if
their understanding of the trial is sufficient to meet a reasonable
standard of informed consent. If adequate levels of knowledge
about the trial cannot be demonstrated, the trial should either be
stopped or, preferably, its informed consent process should be
redesigned to address the deficiencies identified in the survey. In
the absence of real measurements of the outcomes of the informed
consent process, the claim that informed consent was given will be
an empty one, particularly given the well-documented examples of
unacceptably low levels of informed consent in several recent
developing country studies.
Material in Volume II of the NBAC report suggests widespread
support for the concept of incorporating tests of participant
understanding into the research process. Eighty-three percent of
responding international researchers and 65% of U.S. researchers
favored such tests, although only 27% of international and 16% of
U.S. researchers had actually administered them. CIOMS is missing
a golden opportunity to actually advance the ethical conduct of
clinical trials.
Finally, the draft would have researchers provide effective
interventions after the trial "unless the ethical review committee
agrees that there are good reasons not to do so." This is far too
vague. At a minimum, this exception should be restricted to "good
scientific reasons." It would be still better if the document clearly
spelled out a very limited exception here.
Guideline 10: Obligations of researchers regarding informed consent
(Old Guideline 3)
The draft document would create an exemption from the informed
consent requirement for emergency situations. Here, again, the
DOH is being watered down. Considering its length, the CIOMS
document has very little to say about the procedural safeguards for
this rare circumstance. Moreover, the DOH clearly requires,
appropriately, that "Research on individuals from whom it is not
possible to obtain consent, including proxy or advance consent,
should be done only if the physical/mental condition that prevents
obtaining informed consent is a necessary characteristic of the
research population." (Article 26) This wise admonition is missing
from the CIOMS document.
We note, too, that the clear requirement in the DOH that
independent physicians obtain consent when the potential
participant is also a patient of the physician-researcher (Article 23)
is lacking in the draft CIOMS document.
Guideline 19: Safeguarding confidentiality (Old Guideline 12)
Under the draft CIOMS Guidelines, researchers must assure
confidentiality of research data, but the phrase "during the research
process" has now been added. There can be no justification for
this. Certainly, researchers can not be expected to retain research
records indefinitely, but the requirement to protect confidentiality
should extend indefinitely, beyond the life of the research project.
Guideline 20: Right of subjects to compensation (Old Guideline 13)
This Guideline again ushers in a change guaranteed to put a smile
on the faces of the research industry. While the current CIOMS
document requires that compensation for injuries incurred during
the study must be provided and that "The right to compensation
may not be waived," the draft allows IRBs to waive this
entitlement. There is no attempt to justify this proposed change,
except the observation in the commentary accompanying the
Guideline that "in some societies this right to compensation is not
acknowledged." While this is no doubt true, the failure of a country
to require a particular practice (e.g., having an IRB) does not
prevent foreign (or local) researchers from insisting upon it.
Guideline 22: Ethical review of externally sponsored research (Old
Guideline 15)
We are gratified to see that the draft, more clearly than the current
version, requires review by IRBs in both sponsoring and host
countries. If actually followed, this would represent a marked
improvement over current practices: only 22% of
pharmaceutical/biotech studies in developing countries received
review from a U.S. IRB, according to the NBAC.19 The NBAC
report also makes clear that at present many developing countries
(and some industrialized ones) have inadequate capacity for ethical
review.
However, the commentary accompanying the Guideline
contemplates a kind of division of responsibility in which the
industrialized country IRB would merely be responsible for "ensuring
compliance with broadly stated ethical standards," while the
developing country IRB would be reviewing the "detailed plans for
compliance." This might make sense in some ideal world where we
know longer needed the capacity building the document
acknowledges is necessary in Guideline 21. But developing country
researchers who responded to the NBAC survey (approximately 200
of 500 or 40%) indicated that U.S. IRBs were more likely than
developing country IRBs to indicate that confidentiality protections
in the index study were inadequate (42% [U.S.] vs. 18%
[developing country]; p=0.005), to comment on the need for a
consent form
in the local language (84% vs. 58%; p=0.0065) and
to raise concerns about the complexity of the informed consent
form (64% vs. 45%; p=0.070). Twenty-five percent of developing
country respondents indicated that their studies were reviewed by
neither the Ministry of Health nor by an IRB or equivalent.19 Full
review by IRBs in all involved countries is therefore necessary.
Guideline 23: Obligations of external sponsors to provide
health-care services (New Guideline)
It is progress of a sort that a new Guideline addressing this issue
has been added. But the Guideline raises as many questions as it
answers. For one thing, it states that, despite the plea for capacity
building in Guideline 21, providing such services is merely "morally
praiseworthy," not ethically mandatory. For another, it is clearest
on the requirement to refer patients for treatment for diseases
unrelated to the research. Of course, what has raised much
controversy lately has been the treatment of diseases that are
related to the research. These include the provision of antiretroviral
drugs to participants who become infected during HIV vaccine trials
and in studies that monitor HIV progression. This is where the
researcher's conflict of interest arises and where a clear CIOMS
statement of the need to treat such conditions would be helpful.
Conclusion
We are not surprised that the CIOMS and ICH documents are so
much weaker than the DOH. Particularly in the latter phases of the
DOH revision, there were multiple opportunities for public input and
the revisions were put to a vote of the full membership. In contrast,
the ICH consists entirely of the regulatory agencies and
pharmaceutical industries of Europe, the U.S. and Japan. CIOMS is
an organization without clear membership criteria and no
accountability which has met and developed drafts of this
document over a period of two years in complete secrecy, all the
while excluding those known to disagree with the intent of the
research industry. The draft CIOMS document is concerned with
the process of research; without considerably more transparency in
the process of drawing up this research ethics document, it will
have little credibility.
Yours sincerely,
Peter Lurie, MD, MPH
Deputy Director
Sidney M. Wolfe, MD
Director
Public Citizen's Health Research Group
1. World Medical Association Declaration of Helsinki: ethical
principles for medical research involving human subjects. Adopted
by the 18th World Medical Assembly, Helsinki, 1964 and revised by
the 29th World Medical Assembly, Tokyo, 1975, the 35th World
Medical Assembly, Venice, 1983, the 41st World Medical
Assembly, Hong Kong, 1989, the 48th World Medical Assembly,
Somerset West, 1996 and the 52nd World Medical Assembly,
Edinburgh, 2000.
2. International Conference on Harmonisation. Choice of Control
Group in Clinical Trials. Available at:
http://www.ifpma.org/ich5e.html#Design.
3. Lurie P, Wolfe SM. Comments on Draft Guidance on Choice of
Control Group in Clinical Trials. Available at:
http://www.citizen.org/hrg/PUBLICATIONS/1503.htm.
4. Boyd EA, Bero LA. Assessing faculty financial relationships with
industry: a case study. Journal of the American Medical Association
2000;284:2209-14.
5. Birch DM, Cohn G. The changing creed of Hopkins science.
Baltimore Sun, June 25, 2001.
6. Barnes DE, Bero LA. Why review articles on the health effects of
passive smoking reach different conclusions. Journal of the
American Medical Association 1998;279:1566-70.
7. Cho MK, Bero LA. The quality of drug studies published in
symposium proceedings. Annals of Internal Medicine
1996;124:485-9.
8. Dame L, Mendelson LS, Wolfe SM. Letter to U.S. Food and Drug
Administration on Financial Disclosure by Clinical Investigators,
April 29, 1996. Available at:
http://www.citizen.org/hrg/PUBLICATIONS/1390.htm.
9. Johnson RE, Eissenberg T, Stitzer ML, Strain EC, Liebson IA,
Bigelow GE. A placebo controlled clinical trial of buprenorphine as a
treatment for opioid dependence. Drug Alcohol Dependence
1995;40:17-25.
10. Lallemant M, Jourdain G, Le Coeur S, et al. A trial of shortened
zidovudine regimens to prevent mother-to-child transmission of
human immunodeficiency virus type 1. New England Journal of
Medicine 2000;343:982-91.
11. Shapiro HT, Meslin EM. Ethical issues in the design and
conduct of clinical trials in developing countries. New England
Journal of Medicine 2001;345:139-42.
12. Lurie P, Wolfe SM, Klaus M. Letter to Tommy Thompson,
Secretary of Health and Human Services regarding unethical
surfactant trial in Latin America. Available at:
http://www.citizen.org/hrg/publications/1558.htm.
13. Gong L Zhang W, Zhu Y, et al. Shanghai trial of nifedipine in
the elderly (STONE). Journal of Hypertension 1996;14:1237-45.
14. Angell M; Kassirer JP. Alternative medicine -- the risks of
untested and unregulated remedies. New England Journal of
Medicine 1998;339:839-41.
15. Pelton T. Asthma study violated safety rules, FDA says.
Baltimore Sun, July 3, 2001.
16. Karim QA, Karim SSA, Coovadia HM, Susser M. Informed
consent for HIV testing in
a South African hospital: is it truly informed and truly voluntary?
American Journal of Public Health 1998;88:637-40.
17. Sloat B, Epstein K. Living proof: Ugandans in American-run
study expected treatment, but some pills were dummies. Cleveland
Plain Dealer, November 9, 1998, pp. 1-A, 8-A, 9-A.
18. French HW. AIDS research in Africa; juggling risks and hopes.
New York Times, October 9, 1997, p. A1, A8.
19. National Bioethics Advisory Commission. Ethical and Policy
Issues in International Research: Clinical Trials in Developing
Countries. Volume II: Commissioned Papers and Staff Analysis.
Bethesda, MD, May 2001.
20. UNAIDS. Ethical Considerations in HIV Preventive Vaccine
Research. Geneva, May 2000.
21. Quinn TC, Wawer MJ, Sewankambo N, et al. Viral load and
heterosexual transmission of human immunodeficiency virus type 1.
New England Journal of Medicine 2000;342:921-9.
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